1-Propynylaminomethyl-6-phenyl-4H-s-triazolo{8 4,3-a{9 {8 1,4{9 benzodiazepines

ABSTRACT

D R A W I N G WHEREIN R is defined as above. The new compounds of formula 11 and their pharmacologically acceptable acid addition salts have both sedative-tranquilizing and antidepressant effects and can be used to treat anxieties and depression in mammals and birds. 1,(((2-propynyl)amino)methyl)-6-phenyl-4H-s-triazolo -(4,3a)(1,4)benzodiazepines of the formula 11:   WHEREIN R, R&#39;&#39; and R1 are hydrogen or alkyl of 1 to 3 carbon atoms, inclusive, and wherein R2, R3, R4 and R5 are hydrogen, alkyl as defined above, fluorine, chlorine, bromine, nitro or trifluoromethyl; ARE PREPARED BY REACTING A 1-HALOMETHYL-6-PHENYL-4H-striazolo(4,3-a)(1,4)benzodiazepine of the formula:   WHEREIN R&#39;&#39;, R1, R2, R3, R4, and R5 are defined as above, and X is chlorine or bromine, with a propargyl amine of the formula:

United States Patent [191 Hester, Jr.

[ 1-PROPYNYLAMINOMETHYL-G-PHENYL- 4H-S-TRIAZOLO 4,3- A]1,4]BENZODIAZEPINES [75] Inventor: Jackson B. Hester, Jr., Galesburg,

Mich.

[73] Assignee: The Upjohn Company, Kalamazoo,

Mich.

[22] Filed: Mar. 21, 1974 211 App]. No.: 453,194

Primary Examiner-Alton D. Rollins Attorney, Agent, or Firm-Hans L.Berneis [57] ABSTRACT I,[[(2-propynyl)amino]methyl]'6-phenyl-4H-striazolo-[4,3-a][1,4]benzodiazepinesof the formula T T mammal-011% R5 R1 ll [451 July 1,1975

wherein R, R and R are hydrogen or alkyl of 1 to 3 carbon atoms,inclusive, and wherein R R;,, R, and R are hydrogen, alkyl as definedabove, fluorine, chlorine, bromine, nitro or trifluoromethyl;

are prepared by reacting a 1-halomethy1-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine of the formula:

Xll N wherein R, R R R R and R are defined as above, and X is chlorineor bromine, with a propargyl amine of the formula:

HN- CH C' CH wherein R is defined as above.

The new compounds of, formula 11 and their pharmacologically acceptableacid addition salts have both sedative-tranquilizing andgantidepressanteffects and can be used to treat anxieties and depression in mammals andbirds.

14 Claims, No Dgawings 1-PROPYNYL'AMINOMETHYL-6-PHENYL-4H-S-'TRIAZOLO[4,3-A] [1 ,4]BENZODIAZEPINES BACKGROUND or THE INVENTION l.Field of the Invention This invention is directed to new organiccompounds and is more specifically concerned with l-[[(2-propynyl)amino]alkyl]-6-phenyl-4H7s-triazolol4,3- all 1,4l-benzodiazepines of formula l l and a process of production therefor.

The novel compounds of formula 1 l and the process of productiontherefor can be illustratively represented as follows:

llA

wherein R and R' are hydrogen or methyl, wherein R g is hydrogen.chlorine or fluorine, wherein R;, is hydrogen, or fluorine, providing Ris fluorine, and wherein R, is chlorine, fluorine, .bromine, trifluoromethyl and mud, and the pharmacologically acceptable acid addition saltsthereof. I

The most desirable compounds have the formula 1 13 below:

TH RIIH HC= C- CH2-NCH%N,\N N

I l B H '"CH3'(; U1'

wherein R is defined as hereinbefore, in an inert organic solvent and inthe presence of potassium iodide to give a compound of formula 1.1above.

DESCRIPTION OF THE PREFERRED EMBODIMENT Alkyl groups of 1 to 3 carbonatoms, inclusive; are

exemplified by methyl, ethyl, propyl, and isopropyl.

The novel compounds of formula ll (including formula 1 IA and 1 1B) andthe acid addition salts thereof have sedative, tranquilizing andantidepresant effects in mammals and birds.

The acid addition salts of compounds of formula 1 l contemplated in thisinvention are the hydrochlorides, hydrobromides, hydriodides, sulfates,phosphates, cyclohexanesulfamates, methanesulfonates, and the like,prepared by reacting a compound of the formula 11 with thestoichiometrically calculated amount of the selected pharmacologicallyacceptable acid.

Sedative effects of these compounds of formula 1 1 (including compound 11A and 11B) are shown by the following tests in mice:

Chimney test: [Med. Exp 4, (1961)]:

The test determines the ability of mice to back up and out of averticalglass cylinder within 30 seconds. At the effective dosage, 50%of the mice failed doing it.

Dish Test: Mice in Petri dishes l0 cm. diameter, 5 cm high, partiallyembedded in wood shavings), climb out in a very short time, when nottreated. Mice remaining in the dish for more than 3 minutes indicatestranquilization. Ell-,0 Cquals the dose of test compound at which 50% ofthe mice remain in the dish.

Pedestal test: The untreated mouse leaves the pedestal in less than anminute to climb back to the floor of the standard mouse box.Tranquilized mice will stay on the pedestal for more than 1 minute.

Nicotine antagonism test: Mice in a group of6 are injected with the testcompound. Thirty minutes later the mice [including control (untreated)mice] are injected with nicotine salicylate (2 mg./kg.). The controlmice show overstimulation, i.e., (1) running convulsions followed by (2)tonic extensor fits; followed by (3) death.

The antidepressant effects are tested by the standard test in the art:The antagonism to body temperature lowering by oxotremorine, and thesynergistic increase of the lethality ofa standard dose of yohimbine inmice. as well as the synergistic apomorphine gnawing test. The compoundswere found to be active in these tests.

The pharmaceutical forms contemplated by this invcntion includepharmaceutical compositions suited for oral, parenteral, and rectal use,e.g., tablets, powder packets, cachets, dragees, capsules, solutions,suspensions, sterile injectable forms, suppositories, bougies, and thelike. Suitable diluents or carriers such as carbohydrates (lactose),proteins, lipids, calcium phosphate, cornstarch, stearic acid.methylcellulose and the like may be used as carriers or for coatingpurposes. Water and oil. e.g., coconut oil, sesame oil, safflower oil,cottonseed oil, or peanut oil, may be used for preparing solutions orsuspensions of the active drug. sweetening, coloring, and flavoringagents may be added.

For mammals and birds food premixes with starch, oatmeal, driedfishmeat, fishmeal, flour, and the like can be prepared.

As tranquilizer-antidepressant the compounds of formula 1 l and saltsthereof can be used in unit dosages of 0.02 mg./kg. to 5.0 mg./kg.,preferably from 0.1-2 mg./kg., in oral or injectable preparations asdescribed above, to alleviate tension and anxiety in mammals, or birds,such as e.g., occurs when animals are in travel. For larger mammals (5kg. or over) the lower dosages ranges are preferred.

Other acid addition salts of the compounds of formula l 1 can be madesuch as the fluosilicic acid addition salts which are usefulmothproofing compounds or the trichloroacetates useful as herbicidesagainst Johnson grass, Bermuda grass, yellow foxtail and green foxtail,and quack grass.

The starting materials of formula 1 of this invention, are prepared asshown in the Preparations.

ln carrying out the process of this invention, a compound of Formula lis reacted with an excess of a selected propargyl amine of the formula:

H-N-CH -CECH ment of this reaction, an alkali metal iodide, potassium orsodium iodide, is used to catalyze the reaction. After the reaction isterminated, the product is obtained by conventional means, such asextraction, evaporation of the extract, and crystallizing the solids.Further conventional means can be used to purify the product, e.g.,recrystallization and chromatography.

The following Preparations and Examples are illustrative of the productsand the process of the present invention, but are not to be construed aslimiting. Preparation 1 7-Chloro-5-phenyl-3H-l ,4- benzodiazepin-Z-ylhydrazine A stirred mixture of 7-ch1oro-1,3-dihydro-5-phenyl-21-1-1,4-benzodiazepine-2-thione (5- g., 0. l 74 mole) G. A. Archer, J.Org. Chem. 29 231 (1964) and methanol (1700 ml.) was treated withhydrazine hydrate (34.9 g.) and allowed to remain at ambient temperaturefor 1 hour 45 minutes. A slow stream of nitrogen was bubbled through themixture during this period. The resulting solution was concentrated invacuo at 2530C. The thus obtained residue was mixed with water andextracted with chloroform. The extract was dried over anhydrouspotassium carbonate and concentrated under reduced pressure on therotary evaporator in such a manner that the chloroform was replaced byethyl acetate. The resulting mixture was crystallized at 4C. to give26.6 g. of 7-chloro-5-phenyl-3H-l ,4- benzodiazepin-Z-yl hydrazine ofmelting point 184-186C. and 3.04 g. of melting point 204-21 1 C. (60%This compound decomposes on heating in solvents to an unknown product,melting point 261-262 C. The analytical sample was crystallized fromethyl acetate and had a melting point 2l7.52l9C. Anal. calcd. for C HClN C, 63.27; H, 4.60; Cl, 12.45; N 19.68. Found:

C, 63.30; H, 4.52; Cl, 12.46; N, 18.86. Preparation 28-Chloro-1-(chloromethyl)-6-penyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine7-Chloro-5-phenyl-3H-1,4-benzodiazepin-2-yl hydrazine [14.2 g., 0.05mole) was added slowly to acetic acid (150 ml.) with external cooling. Asolution of chloroacetyl chloride (5.65 g.) in acetic acid (75 ml.) wasthen added during 10 minutes, and the red solution was stirred atambient temperature for 1.5 hours, treated with sodium acetate (4.1 g.)stirred again for 30 minutes and then refluxed for 3 hours and 15minutes. This mixture was cooled,- poured into ice water andconcentrated to a small volume. It was then diluted with water,neutralized with sodium bicarbonate and extracted with chloroform. Theextract was dried over anhydrous magnesium sulfate, concentrated and theresidue chromatographed on silica gel (1 kg.) with 1% methanol-99%chloroform. The product obtained from the column was crystallized fromethyl acetate to give 6.36 g. of8-chloro-l-(chloromethyl)-6-phenyl-4H-striazolo[4,3-a]l1,4]benzodiazepine.The analytical sample had a melting point 183l86.5 C. 1 Anal. calcd. forC, H, ,C1 N

C, 59.49; H, 3.53;C1, 20.66; N,. 16.33

Found:

C, 59.59; H, 3.31; C1, 20.21; N, 16.42. Preparation 3 8-Chlorol-(bromomethy1 )-6-phenyl- 4H-s-triazolo[4,3-a][ 1.4]benzocliazepine Inthe manner given in Preparation 2, 7-chloro-5-phenyl-3H-1,4-benzodiazepin-2-yl hydrazine was reacted with bromoacetylchloride and after 1.5 hours with sodium acetate, then refluxed to give8-chloro-lbromomethyl-6-phenyl-4H-triazole[4,3- a][ 1,4]benzodiazepine.Preparation 4 8-chlorol a-chloroethyl )-6-phenyl- 4H-s-triazolo[4,3-a[ l,4]benzodiazepine 7-chloro-5-phenyl-3H-l .4-benzodiazepin2-yl hydra zine(2.85 g., 0.01 mole) was added, under nitrogen, with cooling andstirring to glacial acetic acid (30 ml.). A solution of2-chloropropi0nyl chloride in acetic acid ml.) was then added dropwise,and the resulting red solution was stirred at room temperature for 1.5hours, treated with sodium acetate (0.82 g., 0.01 mole), stirred for anadditional minutes and then refluxed for 2 hours. This mixture wascooled, poured into ice water and concentrated to a small volume. Theresidual solution was neutralized with sodium bicarbonate and extractedwith methylene chloride. The extract wasdried over anhydrous magnesiumsulfate and concentrated. The residue was chromatographed on silica gel(400 g.) with 1% methanol 99% chloroform. The product thus obtained wascrystallized from a small amount of ethyl acetate to give 1.39 g. of 8-chloro-1-(oz-chloroethyl)-6phenyl-4H-s-triazolo-[4,3-a][l,4]benzodiazepine of melting point l53.5l56.5

C Anal. calcd. for C ,;l-l Cl N C, 60.52; H, 3.95; Cl, 19.85; N, 15.68.Found:

C, 60.34 H, 4.07; Cl, 19.81; N, 15.65.

Preparation 58-Fluoro-l-(a-bromoethylJ-6-(ochlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine In the manner given in Preparation 4,7-fluoro5-(ochlorophenyl)-3H-l,4-benzodiazepin-2-yl hydrazine wasreacted with 2-bromopropionyl chloride, and after 1.5 hours with sodiumacetate the mixture was then refluxed to give8-fluoro-l-(oz-bromoethyl)6-(ochlorophenyl)-4H-s-triazolo[4,3-

a][ 1,4]benzodiazepine.

Preparation 6 8-Trifluoromethyl-l-(a-chloroethyl)-6-(o'chlorophenyl)-4H-s-triazolo[4,3-

a][ l,4]benzodizaepine.

In the manner given in Preparation 4,trifluoromethyl-5-(o-chlorophenyl)-3H-1,4- benzodiazepin-Z-yl hydrazinewas reacted with a-chloropropionyl chloride and after l.5 hours withsodium acetate, then refluxed to giveS-trifluoromethyl-l-(achloroethyl)-6-(o-chlorophenyl)-4H-s-triazolo-[4,3-a][ 1,4]benzodiazepine.

Preparation 78-chloro-l-(chloromethyl)-6-(ochlorophenyl)-4H-s-triazolo[4,3- a][1,4]benzodiazepine.

In the manner given in Preparation 2, 7-chloro-5-(o chlorophenyl )-3H- 1,4-benzodiazepin-2-yl hydrazine was'reacted with chloroacetyl bromideand after 1.5 hours with sodium acetate. The mixture was then refluxedto give 8-chloro-l-(chloromethyl)-6-(ochlorophenyl)-4H-s-triazolo[4,3-

a][ l ,4]benzodiazepine.

Preparation 88-Fluoro-l-(chloromethyl)-6-(ofluorophenyl)-4H-s-triazolo[4,3-

a][ 1,4]benzodiazepine.

In the manner given in Preparation 2, 7-fluoro-5-(ofluorophenyl )-3H-l,4-benzodiazepin-2-yl hydrazine was reacted wtih chloroacetyl chlorideand after 1.5 hours with sodium acetate. The mixture was then refluxedto give 8-fluoro-l-(chloromethyl)-6-(o- 6 fluorophenyl )4H-s-triazolo4,3- a][ 1,4]benzodiazepine. Preparation 98-Chloro-l-(chloromethyl)-6-(2,6- difluorophenyl)-4H-s-triazolo[4,3- a][1,4]benzodia2epine.

In the manner given in Preparation 2, 7-chlor0-5-(2,6-difluorophenyl)-3H-1,4-benzodiazepin-2-yl hydrazine was reactedwith chloroacetyl chloride and after 1.5 hours with sodium acetate, thenthe mixture was refluxed to give 8-chloro-l-(chloromethyl)-6-(2,6-difluorophenyl)-4l-l-s-triazolo[4,3-

a][ l ,4]benzodiazepine.

Preparation 10 8-Nitrol bromomethyl )-6-(ochlorophenyl)-4H-s-triazolo[4,3-

a][ 1,4]benzodiazepine.

In the manner given in Preparation 2,7-nitro5-(ochlorophenyl)-3H-1,4-benzodiazepin-2-yl hydrazine was reactedwith bromoacetyl bromide and after l.5 hours with sodium acetate, thenrefluxed to give 8-nitro-l-(bromomethyl)-6-(o-chlorophenyl)-4H-striazolo[4,3-a][ l,4]-benzodiazepine.

Preparation lll-chloromethyl-7-trifluoromethyl-6-(ofluorophenyl)-4H-s-triazolo[4,3-a][ 1,4]benzodiazepine.

In the manner given in Preparation trifluoromethyl-5-(o-fluorophenyl)-3H-l ,4- benzodiazepin-Z-yl hydrazine was reacted with chloroacetylchloride and after 1.5 hours with sodium acetate, then refluxed to givel-(chloromethyl)-7-triflu0romethyl-6'(o-fluorophenyl)-4H-s-triazolo[4,3- a][1,4]benzodiazepine.

In the manner given in the prior preparations other starting compoundsof formula 1 can be prepared. Representative compounds of formula I,thus prepared, comprise:

l-(chloromethyl)-8-bromo-6-phenyl-4H-striazolo[4,3-a]-[ l,4]benzodiazepine,l-(a-chloropropyl)-8-chloro-6-phenyl-4H-striazolo[4,3-a]-[1,4]benzodiazepine,l-(a-chloroethyl)-8-fluoro-6-(o-chlorophenyl)-4l-l-striazolo[4,3-a][ l,4]benzodiazepine,

s-triaz0lo[4,3-a][ 1,4]benzodiazepine,l-(chloromethyl)-7-nitro-6-(m-chlorophenyl)-4H-striazolo-[4,3-a][1,4]benzodiazepine,l-(chloromethyl)-9-nitro-6-(p-nitrophenyl)-4H-striazolo-[4,3-a][1,4]benzodiazepine,l-(chloromethyl)-7-bromo-6-(o-methylphenyl)-4H- s-triazolo-[4,3-a][l,4]benzodiazepine, 1-(a-chloroethyl)-lO-methyl-6-(o-propylphenyl)-4H-s-triazolo[4,3-a][ 1,4]benzodiazepine,l-(a-chloropropyl)-9-isopropyl-6-(misopropylphenyl)-4H-s-triazolo[4.3-a][ 1,4]benzodiazepine, l-(chloromethyl)-8-nitro-6-(2,6-difluorophenyl)-4H s-triazolo[4,3-a][ l ,4]benzodiazepine,l-(achloroethyl)-8-nitro-6-(2,6-difluorophenyl)-4l-l-striazolo[4,3-a][1,4]benzodiazepine,l-(chloromethyl)-8-trifluoromethyl-6-(ofluorophenyl )-4H-s-triazolo[4,3-a][ 1,4]benzodiazepine,

l-( a-bromoethyl )-8-nitro-6-( o-chlorophenyl)-4H-striazolo[4,3-a][1,4]benzodiazepine, and the like.

EXAMPLE 1 8-Chlorol [2-(propynyl )amino]methyl]-6-phenyl-4H-s-trizolo[4,3-a][ 1,4]benzodiazepine. A stirred mix- 7 ture ofl-(chloromethyl)-8-chloro-6-phenyl-4H-striazolo[4,3-a][1,4]benzodiazepine(3.43 g, 0.01 mole), potassium iodide (1.66 g, 0.01 mole), propargylamine 1.10 g, 0.02 mole) and dimethyl formamide (50 ml) was kept atambient temperature, under nitrogen,,

for 12 hours, and concentrated in vacuo. The residue was mixed withwater and extracted wtih methylene chloride. The extract was washed withwater, dried over anhydrous sodium sulfate, and concentrated.Crystallization of the residue from methanol ethyl acctate gave a smallamountof a solid of melting point 155-158 C. dec. The mother liquorwasconcentrat'ed and chromatographed on silica gel (300 g) with amixture of 2.5% methanol-97.571 chloroform. The product thus obtainedwas crystallized from methylene chloride to give 1.62 g. of8-Chloro-1-1'[(2-propyny1) amino]methyl]-6-phenyl 4H-s-triazolo[4,3-a][1,4]benzodiazepine of melting point 193195.5 C.

and 0.38 g, of melting point 190194 C. The analytical sample had meltingpoint 193195.5 C. Anal. Calcd. for CguHf ClNm C, 66.39; H, 4.46; Cl,9.80; N, 19.36 Found:

C, 66.27; H, 4.54; Cl, 10.05; N, 19.66.

EXAMPLE 2 8-Chloro-1-[ 1-l(2-propyny1)arnino]ethyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine. i

A stirred mixture of 1-(a-chloroethyl)-8-ch|oro-6-phenyl-4H-s-triazolol4,3-a]l1,4]benzodiazepine (3.57 g, 0.01 mole),propargylamine (1.10 g, 0.02 mole), potassium iodide (1.66 g; 0.01 mole)and dimethylfo'rmamide (50 ml) was kept at ambient temperature C) for 24hours and concentrated in vacuo. The residue was mixed with water andextracted with methylene chloride. The extract was washed with water;dried over anhydrous sodium sulfate and concentrated. The residue waschromatographed on silica gel (300 g) with 2.5% methanol-97.5%chloroform. The resulting product was crystallized fromethylacetzite-Skellysolve B hexanes to give 1.25 g. of8-chloro-1-[l-[(2- propynyl)amino]ethyl]-6-phenyl-4H-s-triazolo[4.3-a]-[1,4]benzodiazepine of melting point 1471'51 C.,

0.45 g, of melting point '142146 C. and 0.13 "g of melting point 13l-139C. The analytical sample had melting point l46-l52. Anal. calcd. for C HClN C, 67.10; H, 4.83; Cl, 9.43; N, 18.63 Found:

C, 67.15; H, 4.86; Cl, 9.47; N,18.97.

EXAMPLE 3 8 phenyl-4H-s-triazolo[4,3-a][ l,4]-benzodiazepinehydrochloride (1.34 g) of melting point 228-230 C (dec.) and.0.07 g, ofmelting point 230- 232 C (dec.) The analytical sample: hadmeltin'g'point 231232 dec. 7 1 I Anal. Calcd. for C' H Cl N C. 61.17; H,4.64; C1, 17.20; N, 16.99

Found: t I

C, 60.72; H, 4.72; C1, 17.08; N, 16.87

EXAMPLE 4:

8-ch1oro1[l(2-propyny1)amino]methyl]-6-(ochlorophenyl)-4H-s-triazolo[4,3-i a] 1 .4]benzodiazepine 1 1n the manner given" in Example- 1,'8-chloro-l- (chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3- a][ 1,41-benzodiazepine in dimethylformamide was reacted at room temperaturewith propargylamine in the presence of potassium iodide to give8-chloro-1-[[(2- propynyl )amino]-methyl ]-6-(o-chlorophenyl)-4H-striazolo[4,3-a]['1,4]-benzodiazepine.

. EXAMPLE 5 EXAMPLE 7 S-trifluoromethyl-1-[[methyl(2 propynyl)amino]-benzodiazepine In the manner given in Example 1, 8-trifluoroniethyll-(a-ch1oromethyl )-6-(o-ch1orophenyl)-4H-strizo1o[4,3-a]-[1,4]benzodiazepine' in dimethylformamide wasreacted at room temperature with N- methylpropargylamine in the presenceof potassium iodide to give 08-trifluoromethyl-'l-[[methyl(zpropynyl)aminolmethyl]-6-(o-chlorophenyl)-4H-striazo1o-[4,3-a][ 1,4]benzodiazepine I ExAMPLE8 8chloro-l-[1-[(2propynyl)amino]ethy1]-6-(ochlorophenyl )-4H-s=triazolol4,3-' i a][1 ,4]benzodiazepine lnthe manner given in Example 1,8-chloro-l-(achloroethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine in dimethylformamide was re acted at roomtemperature with propargylamine in the presence of potassium iodide togive 8-chloro-I-l l-[(2-propynyl)amino]-ethyl]-6-(ochlorophenyl)-4H-striazolo[4,3-a][1.4]benzodiazepine.

EXAMPLE 9 8-chlorol-[ I-[methyl(2-propynyl)aminolethyll-fil(o-chlorophenyl)'4I-I-s-triazolo{4,3- a][ 1,4]benzodiazepine In themanner given in Example I, 8-chIoro-1-(ozchloroethyl]-6(o-chlorophenyl)-4H-s-triazoIo[4,3-' a][ l ,4]-benzodiazepine indimethylformamide was reacted at room temperature with N-methylpropar'gylam'ine in the presence of potassium idide I to give8-chloro-l-[l-[methyl(2-propynyl)amino]ethyl]-6-(o-chlorophenyl)-4I-I-striazolo[4,3-a][1,4]benzodiazep'ine EXAMPLE 10 triazolo[4,3-a][1,4-ben2bdiazpine indimethylform- EXAMPLE 12 8-Nitroll-[(Z-propynyl)amino]ethyl]-6-(ochlorophenyl)-4H s-triazolo[4,3-a][l,4]benzodiazepine.

In'the manner given in Example I,8-nitro-l-(abromoethyl)-6-(ochlorophenyI)-4I-I-s-triazolo[4,3-a]-[l,4]benzodiazepine in dirnethylformamide was reacted at roomtemperature'with propargylamine in the presence of potassium iodide togive 8-nitro-I-[(2-propynyl)amino]-ethyll-6-(o-chlorophenyl)-4I-I-striazolo[4,3-a][1.4]benzodiazepine.

EXAMPLE 13 8-Nitro-l[[methyl(2-propynyl)amino]methyl]-6-(o-chlorophenyl)-4I-I-s-triazolo[4,3-

a][ 1,4]benz0diazepine.

In the manner given in Example 3, 8-nitro-l (bromomethyl)-6-(o-chlorophenyl)-4H-s-triaz0lo[4,3- a][l,4]benzodiazepine indimethylformamide was reacted at room I temperature with N-methylpropargylamine in:the presence of potassium iodide to giveS-nitro-1-[[methyl(2-pr0pynyl)-amino]methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3- a]1,4]benzodiazepine.

EXAMPLE l4 In the manner given in Example I, 7-trifluoromethyl-9-nitro-l-(chloromethyl)-6-(o-'nitrophenyl)-4H-striazolo-[4,3-a][1,4]benzodiazepinein dimethylformamide was reacted at room temperature with propargylaminein the presence of potassium iodide to give 7-trifluoromethyl9nitrol 2-propynyl)amino]methyl]-6-(o-nitrophenyl)-4II-striazolo[4,3-a][ I,4]benzodiazepine,

EXAMPLE I5 8-chloro-l-ll-[(Z-propynyl)amino]propyl]-6-(ochlorophenyl)-4I-I-s-triazol0[4,3- a][1,4]benzodiazepine.

In the manner given in Example I,8-chlor0-l-(achloropropyl)-6-(ochl0rophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepinein dimethylformamide was reacted at roomtemperature withpropargylamine in the presence of potassium iodide togive 8-chloro-l-[ l -[(2-propynyl)amino]propyl]-6-(o-chlorophenyl)-4H-striazol0[4,3a][1,4]benzodiazepin.

EXAMPLE l6 8-fluoro-I-[l-[(2-propynyl)amino]ethyl]-6-(ochlorophenyl)-4H-s-triazolo[4,3- a][ l,41benzodiazepine.

In the manner given in Example 2,S-fluoro-l-(achloroethyl)-6-(o-chlorophenyl)-4H-s-triaz0lo[4.3-all1,4]benzodiazepine in dimethylformamide was reacted in roomtemperature with propargylamine in the presence of potassium iodide togive S-fluorol-l l-[(2-propynyl)amino]-ethyl]-6-(o-chlorophenyl)-4H-striazolo[4,3-a][1,4]benz0diazepine.

EXAMPLE l7 8-chloro-l-[[methyl(Z-propynyl)amino]methyI]-6-(o-chlorophenyl)-4H s-triazolol4,3- a] I, l ,4]benzodiazepine.

In the manner given in Example 3,8-chloro-lchIoromethyI-6-(o-chlorophenyl)-4H s-triazolo[4,3-a][l,4]benzodia 2epine in dimethylformamide' was reacted at roomtemperature with N- methylpropargylamine in the presence of potassium iodide to give 8-chloro-I-[lmethylt2-propynyl)amino]methyl]-6(o-chlorophenyl)-4H-striazo10[4,3-a]{ l,4lbenzodia zepine,

EXAMPLE l8 S-nitro- I-[ [methy1( 2-propynyl )aminolmethyl1-6-phenyl-4Hs-triazolo[4,3-a][ l,4]benz0diazepine.

In the manner given in Example 3, 8-nitrolchIoromethyI6-phenyl4I-I-s-triazolo[4,3- a][l,4]benzodiazepine indimethylformamide was reacted at room temperature with N-methylpropargylamine in the presence of potassium iodide to give 8- nitro- 1-[[methyl(2-propynyl )amino]methyll-6-phenyl- 4H-s-triazolo[4,3-a][1,4]benzod iazepine.

EXAMPLE l9 8-trifluoromethyl-1-[[methyl(2-propynyl)-amino]methyl]-6phenyl-4H-s-triazolo[4,3- a][ 1,4]benzodiazepine.

In the manner given in Example 3,8-trifluoromethyll-chloromethyl-6-phenyl-4H-s-triazolo[4,3-a][l,4]benzodiazepine in dimethylformamide was re acted at roomtemperature with N- methylpropargylamine in the presence of potassiumiodide to give 8-trifluoromethyll [methyl( 2-propynyl)amino]methyl]-6-phenyl-4H-s-triazolo[4,3- a][1,4]benzodiazepine.

EXAMPLE 2O 8-fluorol [methyl( 2-propynyl )aminolmcthyl 1-6-phenyl-4H-s-triazolo[4,3-21][1,4]benzodiazepine.

In the manner given in Example 3,8-fluorolchloromethyl-6-phenyl-4H-s-triazolol4,3- a][ 1,4]benzodiazepinein dimethylformamide was reacted at room temperature withN-methylpropargylamine in the presence of potassium iodide to give8-fluoro-l-[[methyl(2-propynyl)amino]methyl]-6-pheynl-4H-s-triazolo[4,3-a][ l ,4 ]benzodiazepine.

In the manner given in the preceding examples otherl-alkynylaminoalkyl-6-phenyl-4H-s-triazolo[4,3- a][l,4]-benzodiazepinesof formula ll can be produced. Representative compounds, thus produced,comprise:

8-bromo-l-[[-(2propynyl)amino]methyl]-6-phenyl- 4H-s-triazolo[4,3-a][ l,4]benzodiazepine.

lO-fluoro-1-[[(2-propynyl)amino]methyl]-6-(ofluorophenyl)-4H-s-triazolo[4,3-a][ 1,4]benzodiazepine.

7-nitro-l-[[(Z-propynyl)amino]methyl]-6-(mchlorophenyl)-4H-s-triazolo[4,3-a][ l ,4]benzodiazepine.

9-Nitro-l-[[(2-propynyl)amino]methyl]-6-(pnitrophenyl)-4H-s-triazolo[4,3-a]l l ,4]benzodiazepine.7-bromo-l-[[(2-propynyl)amino]methyl]-6(obromophenyl)-4H-s-triazolo[4,3-a][ l ,4lbenzodiazepine. 4-methyl-l-l l-[(2-propynyl)amino]ethyl]-6-(o-fluorophenyl)-4H-striazolo[4,3-a][ l,4]benzodiazepine. 9-isopropyl-l-[ l-[l-[(2-propynyl)amino]propyl]-6-(misopropylphenyl)-4H-s-triazolo[4,3-a][ 1,4]benzodiazepine. 8-nitro-l-[ [(2-propynyl)amino]methyl]-6-(2,6-difluorophenyl)-4H-striazolo[4,3-a][1,4]benzodiazepine.8-trifluoromethyll-[[(2-propynylamino)methyl]-6-(o-fluorophenyl)-4H-s-triazolol4,3-a][ l ,4]benzodiazepine. 8-bromo-I-[[methyl(2-propynyl)amino]methyl]-6-phenyl-4H-striaZolo[4,3a][ l,4]benzodiazepine. 8-bromo-l-[[ethyl(2-propynyl)amino]methyl]-6-phenyl-4H-striazolo[4,3-a][l,4]benzodiazepine. 8-fluorol[[methyl(2-propynyl)amino]methyl]-6-(ofluorophenyl)-4H-s-triazolo[4,3-a][ 1,4]benzodiazepine. propynyl)amino]methyl]-6-(m-chlorophenyl)-4H-striazolo[4,3-a][1.4]benzodiazepine. 9-nitro-l-[[ethyl(2-propynyl)amino]methyl]-6-(p-nitrophenyl)-4H-s-triazolo[4,3-a][ 1,4]benzodiazepine, 7-bromol[[methyl(2-propynyl)aminolmethyll-b-(ofluorophenyl)-4H-s-triazolo[4.3-a][ 1,4]benzodiazepine. IO-methyll-[methyl( 2-propynyl)amino]methyl]-6-(o-bromophenyl)-4H-striaZoI0[4,3-a][1,4]benzodiazepine.l-[ l-[ethyl(2-propynyl)amino]propyl]-6-(o-chloropheny)-4H-striazolo[4,3-a][1,4]benzodiazepine. S-nitro- 1 [[methyl(2-propynyl)amino]methyl]-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3- I a][ 1,4]benzodiazepine v 7-nitrol[methyl( 2- 8-nitrol ethyl( 2- 12propynyl)amino]methyl]-6-(2,6-difluorophenyl)-4H-striazolo[4,3-a][ l,4]benzodiazepine. 8-nitrol [propyl( 2-propynyl )amino)methyl ]-6-( 2,6difluorophenyl)-4H-s-triazolo[4,3-

a][ 1,4]benzodiazepine. l-[[(2-propynyl)amino]methyll-6-(o-chlorophenyl)-4H-striazolo[4,3-a][ l,4]benzodiazepine. l-[ [methyl( 2-propynyl)amino]methyl]-6-(o-chlorophenyl)-4H-striazolo[4,3-a][1,4]benzodiazepine,and the like.

The pharmacologically acceptable acid addition salts of compounds offormula II (as well as of formula HA and 118) can be prepared andisolated by conventional processes, such as reacting a compound offormula II with a selected pharmacologically acceptable acid. Such acidsinclude hydrochloric, hydrobromic, phosphoric, sulfuric, acetic,tartaric, lactic, citric, malic, maleic, methanesulfonic,benzenesulfonic, cyclohexanesulfamic, toluenesulfonic acids, and thelike. The reaction is conveniently performed in an organic solvent,e.g., ether, dioxane or tetrahydrofuran, ethanol, methanol, or ethylacetate. The salts can be recovered by crystallization, precipitation orevaporating the solvent. These salts are usable in the same manner asthefree bases, discussed hereinbefore.

I claim: 1. A compound of the formula ll wherein R, R and R, arehydrogen or alkyl of l to 3 carbon atoms, inclusive; wherein R R R and Rare hydrogen, alkyl as defined above, fluorine, chlorine, bromine, nitroor trifluoromethyl; and the pharmacologically acceptable acid additionsalts thereof.

2. A compound according to claim 1 of the formula:

able addition salts thereof.

3. A compound according to claim 1 of the formula:

wherein R and R are hydrogen or methyl, and wherein R is hydrogen,chlorine or fluorine and the pharmacological acceptable acid additionsalts thereof.

4. A compound according to claim 3, wherein R, R and R are hydrogen andthe compound is there fore 8-chloro-1-[[(2-propynyl)amino]methyl1-6-phenyl-4H-s-triazolo-[4,3-a][1,4]benzodiazepine.

5. A compound according to claim 3, wherein R" and R are hydrogen, R ischlorine, and the compound is therefore S-chlorol [(2-propynyl)amino]methyl]-6-(o-chlorophenyl)-4H-striazolo[4,3a][1,4]benzodia2epine.

6. A compound according to claim 3, wherein R is methyl, R and R arehydrogen and the compound is therefore8-chloro-l-[l-[(2-propynyl)amino]ethyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.

7. A compound according to claim 3 wherein R" is methyl, R and R arehydrogen and the compound is therefore 8-chloro- 1 [methyl( 2-propynyl)amino]methyl]-6-phenyl-4H-s-triazolo[4,3- a][,4lbenzodiazepine.

8. A compound according to claim 3, wherein R and R are methyl, R ischloro, and the compound is therefore 8-chloro-1-[ 1-[methyl(2-propynyl)amino]ethyll-o-(o-chlorophenyl)-4H-striazolo[4,3-a][1,4]benzodiazepine.

9. A compound according to claim 2, wherein R", R and R;, are hydrogen,R is chlorine, R, is nitro, and the compound is therefore8-nitro-l-[[(2-propynyl)amino]-methyl]-6-(o-chlorophenyl)-4H-striaZolo[4,3-a][1,4]benzodiazepine.

10. A compound according to claim 2, wherein R and R' are hydrogen, R'is methyl, R is chlorine, R, is nitro, and the compound is therefore8-nitro-1-[l[(2propynyl)amino]ethyl]-6-(ochlorophenyl)-4H-striazolo-{4,3-a][1,4]benzodiazepine.

11. A compound according to claim 3, wherein R is hydrogen, R is methyl,and R: is chlorine and the compound is therefore 8-chloro-1-[[methyl(2-propynyl)-amino]methyl]-6-(o-chlorophenyl)-4H-striazolo[4,3-a]-[1,4]benzodiazepine.

12. A compound according to claim 2, wherein R' and R are hydrogen, R ismethyl and R, is nitro and the compound is therefore S-nitro-l-l[methyl(2- propynyl)-amino]methylJ-6-phenyl-4H-s-triazolol4,3- a][1,4]benzodiazepine 13. A compound according to claim 2, wherein R and Rare hydrogen, R" is methyl and R, is trifluoromethyl and the compound istherefore 8- trifluoromethyll [methyl( 2-propynyl)amino]methyl]-6-phenyl-4Hs-triazolol4.3- a][ l,4lbenzodiazepine.

14. A compound according to claim 2, wherein R and R' are hydrogen, R ismethyl and R, is fluoro and the compound is therefore8-fluoro-l-[[methyl(2-propynyl)amino]-methyl]-6phenyl-4H-s-triazolo[4,3- a][1,4]benzodiazepine.

1. A COMPOUND OF THE FORMULA II
 2. A compound according to claim 1 ofthe formula:
 3. A compound according to claim 1 of the formula:
 4. Acompound according to claim 3, wherein R'''', R'''''' and R2 arehydrogen and the compound is therefore8-chloro-1-(((2-propynyl)amino)methyl)-6-phenyl-4H-s-triazolo-(4,3-a)(1,4)benzodiazepine.
 5. A compound according to claim 3, wherein R'''' andR'''''' are hydrogen, R2 is chlorine, and the compound is therefore8-chloro-1-(((2-propynyl)amino)methyl)-6-(o-chlorophenyl)-4H-s-triazolo(4,3-a)(1,4)benzodiazepine.
 6. Acompound according to claim 3, wherein R'''''' is methyl, R'''' and R2are hydrogen and the compound is therefore8-chloro-1-(1-((2-propynyl)amino)ethyl)-6-phenyl-4H-s-triazolo(4,3-a)(1, 4)benzodiazepine.
 7. A compoundaccording to claim 3 wherein R'''' is methyl, R2 and R'''''' arehydrogen and the compound is therefore8-chloro-1-((methyl(2-propynyl)amino)methyl)-6-phenyl-4H-s-triazolo(4,3-a)(1,4)benzodiazepine.
 8. A compound according to claim 3, whereinR'''' and R'''''' are methyl, R2'' is chloro, and the compound istherefore8-chloro-1-(1-(methyl(2-propynyl)amino)ethyl)-6-(o-chlorophenyl)-4H-s-triazolo(4,3-a)(1,4)benzodiazepine.
 9. A compound according to claim 2,wherein R'''', R'''''' and R''3 are hydrogen, R''2 is chlorine, R''4 isnitro, and the compound is therefore8-nitro-1-(((2-propynyl)amino)-methyl)-6-(o-chlorophenyl)-4H-s-triazolo(4,3-a)(1,4)benzodiazepine.
 10. A compound according to claim 2, whereinR'''' and R''3 are hydrogen, R'''''' is methyl, R''2 is chlorine, R''4is nitro, and the compound is therefore8-nitro-1-(1-((2-propynyl)amino)ethyl)-6-(o-chlorophenyl)-4H-s-triazolo-(4,3-a)(1,4)benzodiazepine.11. A compound according to claim 3, wherein R'''''' is hydrogen, R''''is methyl, and R''2 is chlorine and the compound is therefore8-chloro-1-((methyl(2-propynyl)-amino)methyl)-6-(o-chlorophenyl)-4H-s-triazolo(4,3-a)-(1,4)benzodiazepine.
 12. A compound according to claim2, wherein R'''''' and R''2 are hydrogen, R'''' is methyl and R''4 isnitro and the compound is therefore8-nitro-1-((methyl(2-propynyl)-amino)methyl)-6-phenyl-4H-s-triazolo(4,3-a)(1,4)benzodiazepine.
 13. A compound according to claim 2, whereinR'''''' and R''2 are hydrogen, R'''' is methyl and R''4 istrifluoromethyl and the compound is therefore8-trifluoromethyl-1-((methyl(2-propynyl)amino)methyl)-6-phenyl-4H-s-triazolo(4,3-a)(1, 4)benzodiazepine.
 14. A compound according to claim2, wherein R'''''' and R''2 are hydrogen, R'''' is methyl and R''4 isfluoro and the compound is therefore8-fluoro-1-((methyl(2-propynyl)amino)-methyl)-6-phenyl-4H-s-triazolo(4,3-a)(1,4)benzodiazepine.